A continuous flux electrospray or a plasma ion source may produce 1011-1012 charges per second of which up to 1010 or more charges per second are expected to enter the mass analyzer. Ions that are produced in this way can be separated based on their mass-to-charge (m/z) ratios, and then detected to obtain a measure of the number of ions of each m/z ratio. The results of such an analysis are presented typically in the form of a mass spectrum.
In order to maximize sensitivity, all of the ions that are generated in the ion source should be detected at the detector. Unfortunately, this ideal condition is not achieved in practice for a variety of reasons. For instance, conventional sequential mass analyzers such as a quadrupole mass analyzer or a magnetic sector operate as scanning mass filters, which transmit ions within only a narrow range of m/z ratios at a time, and the full mass range of interest is scanned. Ions that have m/z ratios outside of the transmitted range at any given time are discarded without contributing to the detected ion signal, and as a result the analytical throughput is reduced.
Panoramic mass analyzers such as time-of-flight, orbital trapping or Fourier-transform ion cyclotron resonance are able to detect over a wide mass range and this has facilitated their broad acceptance in life science mass spectrometry. However, high complexity of analyzed mixtures requires additional selectivity of analysis that is usually enforced by adding mass filters in order to concentrate on a narrow mass range only. Mass filtering is frequently accompanied by fragmentation of ions in that range and measurement of fragments for purposes of identification and quantitation (so called MS/MS mode). Such instruments yield high-resolution, high mass-accuracy fragment spectra and have been used in accordance with various methods of targeted and untargeted analysis. Of course, while all fragments are analyzed in parallel the different precursor compounds are selected one at a time, and accordingly relatively more time is needed to obtain high-quality spectra of low-intensity precursors. As a result, the practical throughput of such systems remains low.
Other solutions based on multi-channel MS/MS have also been proposed, in which each of a plurality of parallel mass analyzers is used to select one precursor compound and scan out its fragments to an individual detector. Examples of such systems include: the ion trap arrays disclosed in U.S. Pat. No. 5,206,506 or U.S. Pat. No. 7,718,959; the multiple traps disclosed in U.S. Pat. No. 6,762,406; and the multiple TOFs disclosed in US PG-PUB No. 2008/0067349. Such arrays speed up the analysis but typically this is achieved at the cost of poor utilization of the sample stream for each particular element of the array, since each element of the array is filled either sequentially or from its own source.
In a different approach, improved throughput is achieved by separating the ion beam into packets or groups of multiple precursor ion species, each group containing ions having an m/z value or another physico-chemical property (e.g. cross-section) that lies within a window of values, and each group is fragmented without the loss of the other groups, or multiple groups are concurrently and separately fragmented. Such parallel selection potentially supports utilization of the analyte to its full extent. Several configurations have been suggested, including: a scanning device that stores ions of a broad mass range (e.g. a 3D ion trap as disclosed in PCT Publication No. WO 03/103010, or a linear trap with radial ejection as disclosed in U.S. Pat. No. 7,157,698); pulsed ion mobility spectrometer (as disclosed in PCT Publication No. WO 00/70335, US 2003/0213900, U.S. Pat. No. 6,960,761, e.g. so-called time-aligned parallel fragmentation, TAPF); slowed-down linear (WO 2004/085992) or multi-reflecting TOF mass spectrometer (WO 2004/008481); or even magnetic sector instruments.
In all cases, the first stage of ion separation into distinct ion groups based on m/z or cross-sections is followed by fast fragmentation, e.g. in a collision cell (preferably with an axial gradient) or by a pulsed laser. Then fragments are analyzed (preferably by a TOF analyzer) on a much faster time scale than the scanning duration, although performance is constrained by the very limited time that is allocated for each scan (typically, 50-200 μs).
In practice, all such parallel selection methods suffer from one or all of the following drawbacks: relatively low resolution of precursor selection; insufficient space charge capacity of the trapping device (which frequently negates all advantages of parallel separation); cumbersome control of ion populations; relatively low resolving power of fragment analysis; and low mass accuracy of fragment analysis.
Various approaches have been suggested to decouple fragment analysis from parallel selection. In WO 2013/076307, Makarov discusses an ion separator that is based on selective orthogonal ejection of ions from a linear quadrupole RF trap, which is being filled continuously with ions. The ions are released from the RF trap using mass-selective orthogonal alternating-current (AC) excitation at scanning frequency. The separator may be operated with an input ion flux up to about 108 charges per second. Unfortunately, the resolving power is significantly deteriorated due to the space charge that is accumulated in the RF trap.
U.S. Pat. No. 8,581,177 addresses the problems that are associated with ion storage limitations of the trapping devices in parallel selection methods. In particular, a high capacity ion storage/ion mobility instrument is disposed as an interface between an ion source inlet and a mass spectrometer. The high capacity ion storage instrument is configured as a two-dimensional (2D) array of a plurality of sequentially arranged ion confinement regions, which enables ions within the device to be spread over the array, each confinement region holding ions for mass analysis being only a fraction of the whole mass range of interest. Ions can then be scanned out of each confinement region and into a respective confinement cell (channel) of a second ion interface instrument. Predetermined voltages are adjusted or removed in order to eliminate potential barriers between adjacent confinement cells so as to urge the ions to the next (adjacent) confinement cell, and this is repeated until the ions are eventually received at an analyzer. The ions are therefore transported in a sequential fashion from one confinement cell to the next, and as such it is possible only to analyze each group of ions in a predetermined order that is based on the original ion mobility separation. In particular, the approach that is proposed in U.S. Pat. No. 8,581,177 does not support a method of analyzing the confined groups of ions in an on-demand fashion.
This limitation is overcome in US 2015/0287585A1 where an ion storage array of independently operable storage cells allows analysing such confined groups of ion in an on-demand fashion. However, separation of ions into storage cells is also implemented by using a pulsed ion mobility device that requires storage prior to separation.
Unfortunately, all the above-noted methods are based on using trapping devices prior to or integrated with the separator to provide high duty cycle of its operation, and the cycle time is defined by the cycle time of the separator. As mentioned above, modern ion sources produce ion currents in vacuum in the range of hundreds to thousands of pA, i.e. >109 to 1010 elementary charges/second. Assuming a full cycle of scanning through the entire mass range of interest is 5 ms, then such trapping devices should be able to accumulate at least 5-50 million elementary charges and still allow efficient precursor selection.
It would therefore be beneficial to provide a system and method that avoids high space charge building up in the separator as may occur in the prior art devices.